tbuckley/cabot-search huggingface dataset:
NLRC3 expression in macrophage impairs glycolysis and host immune defense by modulating the NF-κB-NFAT5 complex during septic immunosuppression
Authors: Jiqian Xu, Chenggang Gao, Yajun He, Xiangzhi Fang, Deyi Sun, Zhekang Peng, Hairong Xiao, Miaomiao Sun, Pei Zhang, Ting Zhou, Xiaobo Yang, Yuan Yu, Ruiting Li, Xiaojing Zou, Huaqing Shu, Yang Qiu, Xi Zhou, Shiying Yuan, Shanglong Yao, You Shang
Journal: Molecular Therapy (2022)

Impairment of innate immune cell function and metabolism underlies immunosuppression in sepsis; however, a promising therapy to orchestrate this impairment is currently lacking. In this study, high levels of NOD-like receptor family CARD domain containing-3 (NLRC3) correlated with the glycolytic defects of monocytes/macrophages from septic patients and mice that developed immunosuppression. Myeloid-specific NLRC3 deletion improved macrophage glycolysis and sepsis-induced immunosuppression. Mechanistically, NLRC3 inhibits nuclear factor (NF)-κB p65 binding to nuclear factor of activated T cells 5 (NFAT5), which further controls the expression of glycolytic genes and proinflammatory cytokines of immunosuppressive macrophages. This is achieved by decreasing NF-κB activation-co-induced by TNF-receptor-associated factor 6 (TRAF6) or mammalian target of rapamycin (mTOR)-and decreasing transcriptional co-activator p300 activity by inducing NLRC3 sequestration of mTOR and p300. Genetic inhibition of NLRC3 disrupted the NLRC3-mTOR-p300 complex and enhanced NF-κB binding to the NFAT5 promoter in concert with p300. Furthermore, intrapulmonary delivery of recombinant adeno-associated virus harboring a macrophage-specific NLRC3 deletion vector significantly improved the defense of septic mice that developed immunosuppression upon secondary intratracheal bacterial challenge. Collectively, these findings indicate that NLRC3 mediates critical aspects of innate immunity that contribute to an immunocompromised state during sepsis and identify potential therapeutic targets.
Multimodality Therapy in Patients With Primary Pericardial Mesothelioma
Authors: Michael Offin, Dilanka L. De Silva, Jennifer L. Sauter, Jacklynn V. Egger, Ellen Yorke, Prasad S. Adusumilli, Andreas Rimner, Valerie W. Rusch, Marjorie G. Zauderer
Journal: Journal of Thoracic Oncology (2022)
Inducing mismatch repair deficiency sensitizes immune-cold neuroblastoma to anti-CTLA4 and generates broad anti-tumor immune memory
Authors: Mikal El-Hajjar, Lara Gerhardt, Megan M Y Hong, Mithunah Krishnamoorthy, Rene Figueredo, Xiufen Zheng, James Koropatnick, Saman Maleki Vareki
Journal: Molecular Therapy (2022)

Immune checkpoint blockade can induce potent and durable responses in patients with highly immunogenic mismatch repair-deficient tumors; however, these drugs are ineffective against immune-cold neuroblastoma tumors. To establish a role for a T cell-based therapy against neuroblastoma, we show that T cell and memory T cell-dependent gene expression are associated with improved survival in high-risk neuroblastoma patients. To stimulate anti-tumor immunity and reproduce this immune phenotype in neuroblastoma tumors, we used CRISPR-Cas9 to knockout MLH1-a crucial molecule in the DNA mismatch repair pathway-to induce mismatch repair deficiency in a poorly immunogenic murine neuroblastoma model. Induced mismatch repair deficiency increased the expression of proinflammatory genes and stimulated T cell infiltration into neuroblastoma tumors. In contrast to adult cancers with induced mismatch repair deficiency, neuroblastoma tumors remained unresponsive to anti-PD1 treatment. However, anti-CTLA4 therapy was highly effective against these tumors. Anti-CTLA4 therapy promoted immune memory and T cell epitope spreading in cured animals. Mechanistically, the effect of anti-CTLA4 therapy against neuroblastoma tumors with induced mismatch repair deficiency is CD4
Safety, tolerability, and efficacy of pirfenidone in patients with rheumatoid arthritis-associated interstitial lung disease: a randomised, double-blind, placebo-controlled, phase 2 study
Authors: Joshua J Solomon, Sonye K Danoff, Felix A Woodhead, Shelley Hurwitz, Rie Maurer, Ian Glaspole, Paul F Dellaripa, Bibek Gooptu, Robert Vassallo, P Gerard Cox, Kevin R Flaherty, Huzaifa I Adamali, Michael A Gibbons, Lauren Troy, Ian A Forrest, Joseph A Lasky, Lisa G Spencer, Jeffrey Golden, Mary Beth Scholand, Nazia Chaudhuri, Mark A Perrella, David A Lynch, Daniel C Chambers, Martin Kolb, Cathie Spino, Ganesh Raghu, Hilary J Goldberg, Ivan O Rosas, Shana Haynes-Harp, Fernando Poli, Coimbatore Sree Vidya, Rebecca R. Baron, Timothy Clouser, Tracy Doyle, Anthony Maeda, Kristin B. Highland, Jemima F. Albayda, Sarah E. Collins, Karthik S. Suresh, John M. Davis, Andrew H. Limper, Isabel Amigues, Kristina Eliopoulos, Jeffery J. Swigris, Stephen Humphries, John C. Huntwork, Chris Glynn, Steve R. Duncan, Maria I. Danila, Marilyn K. Glassberg, Elana M. Oberstein, Elizabeth A. Belloli, Linda Briggs, Vivek Nagaraja, Linda Cholewa, Donna DiFranco, Edward Green, Christie Liffick, Tanvi Naik, Genevieve Montas, Dorota Lebiedz-Odrobina, Reba Bissell, Mark Wener, Lisa H. Lancaster, Leslie J. Crawford, Karmela Chan, Robert J. Kaner, Alicia Morris, Xiaoping Wu, Nader A. Khalidi, Christopher J. Ryerson, Alyson W. Wong, Charlene D. Fell, Sharon A. LeClercq, Mark Hyman, Shane Shapera, Shikha Mittoo, Shireen Shaffu, Karl Gaffney, Andrew M. Wilson, Shaney Barratt, Harsha Gunawardena, Rachel K. Hoyles, Joel David, Namrata Kewalramani, Toby M. Maher, Philip L. Molyneaux, Maria A. Kokosi, Matthew J. Cates, Mandizha Mandizha, Abdul Ashish, Gladstone Chelliah, Helen Parfrey, Muhunthan Thillai, Josephine Vila, Sophie V. Fletcher, Paul Beirne, Clair Favager, Jo Brown, Julie K. Dawson, Pilar Rivera Ortega, Sahena Haque, Pippa Watson, Jun K. Khoo, Karen Symons, Peter Youssef, John A. Mackintosh
Journal: The Lancet Respiratory Medicine (2022)
P10.14.A Caught in a trap: Silk fibroin, hyaluronic acid, and heparin sponges to capture residual glioblastoma cells
Authors: N H Ferreira, R Molina-Pena, M Najberg, C Roy, L Roncali, S Avril, M H Mansor, F Boury, C Alvarez-Lorenzo, E Garcion
Journal: Neuro-Oncology (2022)

Abstract Background Recurrent glioblastoma (GBM) is today inevitable, even using an aggressive treatment protocol (surgery, radiotherapy, and chemotherapy). It mostly occurs within 2 cm of the resection cavity due to the invasion ability of GBM cells. The aim of this work is to test and qualify a local integrative approach using a nano-based chemokine-cancer cell trap concept to lure the residual GBM cells by releasing chemoattractive molecules and, ultimately, confine and kill them in a biomimetic nanostructured polymeric scaffold. Material and Methods The stromal cell-derived factor 1α (SDF-1α) was used here as a chemoattractant due to its synergy with the CXCR4 receptor, and the correlation of this axis to the migration of infiltrating GBM cells. Freeze-dried sponges (20 to 140μm/pore size) composed of silk fibroin (SF), hyaluronic acid (HA), and heparin (hep) charged with SDF-1α was evaluated as a GBM cell trap. First, the cytocompatibility and biodegradability of the sponges were evaluated both in vitro and vivo. Secondly, molecular and functional responses of GBM cells to SDF-1α treatment were evaluated using U87MG-CXCR4+ cells, that constitutively and stably expressed both the CXCR4 receptor and RFP, as reporters. To assess the cell migration in response to the SDF-1α gradient in vitro, transwell, under-agarose, and agarose drop assays were used. U87MG-CXCR4+ spheroids were cultivated in the sponges to verify the hosting capacity of the scaffolds. Finally, syngeneic and xenogeneic models were developed to evaluate the bioperformance of the sponges in vivo. Results SF-HA-hep sponges presented low cytotoxicity and complete biodegradation after 4 months of implantation. Histological analysis revealed only local reaction, as an immune response in the short-term study, but no signs of acute inflammation or fibrotic process were found at the resection cavity-brain margin in the long-term study, demonstrating fine tolerability in vivo. Relevant molecules involved in chemotaxis (Akt, Erk, and Paxillin) were activated upon treatment with SDF-1α. U87MG-CXCR4+ cells were directionally attracted to the SDF-1α-loaded sponges, and also a larger neurosphere infiltration area was observed in these sponges compared to controls. Preliminary observations have shown cell clusters detached from the main tumor mass towards the cavity with the implanted SDF-1α-loaded sponge. This may be indicative of chemoattraction, as DAPI correlated with Ki67 staining in the migration front. Further analyses including CXCR4, CD44, paxillin, and galectin-1 immunolabeling will be performed to confirm this hypothesis. Conclusion Overall, the results showed that the sponges are biocompatible and the SDF-1α suitable to use as a chemoattractant for GBM cells. This strategy can be used to overcome the treatment resistance in GB, and potentially be transferred to the clinic in the future.
P11.23.B Neurological symptoms independently associate with overall survival in patients with melanoma brain metastases
Authors: A Steindl, K Heimbach, J Ressler, B Gatterbauer, K Dieckmann, G Widhalm, M Preusser, A Berghoff
Journal: Neuro-Oncology (2022)

Abstract Background Based on the the rising detection of asymptomatic brain metastases (BM) and the remarkable intracranial responses of targeted- and immunotherapy in specific subgroups of asymptomatic BM patients, we aimed to evaluate the clinical characteristics and prognostic value of neurological symptoms in BM from melanoma. Material and Methods 670 patients with newly diagnosed melanoma BM were identified from the Vienna Brain Metastasis Registry. We performed retrospective chart review and statistical outcome analyses. Results 370/670 (55.2%) patients presented with neurological symptoms including neurological deficits (316/370; 85.4%), signs of increased intracranial pressure (126/370; 34.1%) and epileptic seizures (53/370; 14.3%). 57.6% (80/139) of patients with BRAF mutated melanoma presented with asymptomatic BM at diagnosis. Absence of neurological symptoms at BM diagnosis was associated with a longer median overall survival after time of BM diagnosis (7 vs. 5 months; p&amp;lt; 0.001; log-rank test). In multivariate analysis with the diagnosis-specific graded prognostic assessment (DS-GPA: HR:1.4; 95% CI, 1.25-1.48; p&amp;lt;0.001) and the graded prognostic assessment for melanoma using molecular markers (Melanoma-molGPA: HR:0.8; 95% CI, 0.66 -0.92; p&amp;lt;0.001), the presence of neurological symptoms (HR 0.8; 95% CI, 0.69 -0.96; p=0.003/ HR:0.6; 95% CI, 0.59-0.72; p&amp;lt;0.001) was found to be independently associated with survival prognosis from time of BM diagnosis respectively. Conclusion: Neurological symptoms at the time of BM diagnosis are an independent and strong prognostic factor in melanoma BM patients. Our results argue for the integration of neurological symptoms into the prognostic assessment of patients with BM from melanoma.
P11.21.B Distinct age-related molecular and clinical features in<i>IDH</i>-Wildtype Glioblastoma
Authors: S Richter, S Stasik, G Schackert, C Thiede, D Krex, T A Juratli
Journal: Neuro-Oncology (2022)

Abstract Background The incidence of IDH-wildtype Glioblastomas (IDH-wt GBM) are highest amongst the elderly. However, IDH-wt GBM can occur in younger patients, subsequently associated with a relatively better prognosis. We aimed for comprehensive molecular characterization of IDH-wt GBM in a cohort with large range of Age at onset (AAO) to investigate age-related molecular patterns with potential impact on clinical tumor features and patients′ outcome. Material and Methods We performed Whole Exome Sequencing (WES) on 55 patients with IDH-wt GBM. Sanger Sequencing was utilized for the TERT-promotor region as well as selected candidate genes to validate the results of the WES. Moreover, Progression-free- and Overall survival (PFS, OS) data, clinical- and tumor features were collected. Results The patients’ median AAO was 58 yrs. (range: 22.9-70.8 yrs.). We divided our study cohort into three subgroups based on AAO quartiles for further analysis: Group A: 22.9-40.4 yrs. (Q1), Group B: 44.5-71.0 yrs. (Q2-3) and Group C: 72.7-79.8 yrs. (Q4). The median OS for all patients was 15.9 months with a PFS of 9.5 months. The median tumor volume at initial presentation was 43.8 cm3 and correlated with AAO: 63.6 cm3 (Group A) vs. 41.2 cm3 (Group C).We identified a median of 32 mutations per tumor. Exome and Sanger sequencing detected frequent alterations on TERT-promoter (76.4%) and EGFR (90.9% gain, 50.1% amplification, 29.1% mutation). Chromosome 7 gain (92.7%) and Chromosome 10 deletion (85.5%) occurred significantly less in younger patients (Group A vs. Groups B/C; p=0.037, p=0.013). However, other individual alterations did not correlate with AAO. Via clustering of various alterations (e.g. TP53, PDGFRA, ATRX), we found an association between a proneural GBM signature and younger AAO (p=0.036). AAO itself had an independent impact on OS: 21.5 Mo. (Group A) vs. 10.1 Mo. (Group C). Moreover, we described TET1-deletions on Chr. 10 in 90.1% of cases, which was not previously described in IDH-wt GBM. Bi-allelic TET1 deletions (32.7%) with concurrent EGFR-amplification had a significant impact on patient’s outcome (OS 12.2 Mo. vs. 17.6 Mo.; p=0.013). Conclusion Although GBM signatures showed subtle association with AAO, our data provides no evidence for an age-specific molecular pattern. The vast amount of detected alterations regardless of AAO underlines the overall heterogeneity of IDH-wt GBM. The cause of better prognosis at younger age remains unclear on a molecular explanatory approach. Finally, a bi-allelic deletion of TET1 may represent a relevant alteration in IDH-wt GBM.
P10.18.A Replication of previous GWAS identifies TERT and near EGFR SNVs as risk factors in EPIC glioma patients: a nested case-control study
Authors: W Wu, A Dahlin, U Andersson, C Wibom, S Jonsson, B Melin
Journal: Neuro-Oncology (2022)

Abstract Background Gliomas, the most common malignant primary brain tumors in adults, typically have a poor prognosis irrespective of medical care. Previous large genome-wide association studies (GWAS) have identified 27 single-nucleotide variants (SNVs) that are significantly associated with glioma. However, most of the GWAS are conducted by case-control study designs, it is therefore prone to bias when rapidly lethal cases don’t have chance to be included in the study. This study aims to replicate the previous GWAS findings using prospective study design. Material and Methods We conducted a nested case-control study within the European Prospective Investigation into Cancer (EPIC) cohort from 7 European countries. GSA-MD Infinium global screening array was used for genotyping. Some subjects were genotyped by other platforms previously. In total, 468 glioma patients and 481 controls were included. The genotypes of 27 SNVs were extracted and for ungenotyped SNVs, datasets were imputed using SHAPEIT v4.1.3 and IMPUTE5 v1.1.5 based on the Haplotype Reference Consortium (Release 1.1) reference panel. Conditional logistic regression model was used to investigate the additive effect of SNVs on the risk of glioma. Results 21 SNVs showed a consistent direction of effect with previous studies, whereas 6 SNVs did not (ORs between 0.72-0.99 and not significant). After adjusting for multiple testing, two SNVs, rs10069690 (TERT), and rs75061358 (near EGFR) were significantly associated with glioma risk. We observed that prominent OR (2.23, 95%CI=1.49-3.33) of rs75061358 in our study compared to the result from previous GWAS, which implied rs75061358 might be not only a risk factor but also affect survival. Different risk direction was observed for rs77633900 in ETFA gene (OR=0.72, 95%CI=0.51-1.01). Conclusion Our findings further confirmed the genetic role on the etiology of glioma in the European population. The potential biases from the previous GWAS are required to be elucidated.
P11.14.A Systematic review of phase III trials in newly diagnosed glioblastoma 2005-2021
Authors: C Oster, L Lazaridis, J Feldheim, T Schmidt, C Kleinschnitz, S Kebir, M Glas
Journal: Neuro-Oncology (2022)

Abstract Background Despite a plethora of studies since the EORTC/NCIC trial in 2005, glioblastoma (GBM) prognosis remains poor. We here identify and compare glioblastoma phase III trials in terms of efficacy and baseline characteristics in an attempt to summarize the experience of the past 16 years. Methods A systematic literature search using PubMed and ClinicalTrials.gov was conducted to provide an overview of clinically relevant GBM phase III trials (years 2005-2021) of adult patients younger than 70 years of age. Search results were screened according to predefined inclusion criteria and either excluded or included in further analysis on study design, baseline characteristics, and survival results. Results Eleven trials from the literature and clinical trial database fulfilled the search criteria. Among these trials, a total of three GBM phase III trials reported overall survival (OS) benefit, including the EORTC/NCIC study (NCT00006353), EF-14 (NCT00916409) and CeTeG/NOA09 (NCT01149109). All three studies demonstrate similar hazard ratios, which translate into risk reduction of about 40%. Furthermore, low toxicity profile and mostly preserved quality of life were attributed to the treatments tested. Looking at the study designs, eight out of eleven trials were open label randomized trials, including all of the positive ones, and only three negative trials employed treatment blinding and a placebo control. Canonical baseline characteristics (extent of resection, age, gender, MGMT promoter methylation status) did not significantly differ between positive and negative trials. IDH mutation status was analyzed in only two trials, each showing a small percentage of IDH-mutant tumors only. Conclusion This analysis on GBM phase III trials conducted between 2005 and 2021 revealed that the majority of trials did not show a significant improvement in overall survival. CeTeG/NOA-09 and EF-14 are the only two studies with positive overall survival outcome since the EORTC/NCIC trial in 2005.
P17.01.A Reradiation by Glioblastoma recurrence with VMAT technique
Authors: M Theodorou, I Polycarpou
Journal: Neuro-Oncology (2022)

Abstract Background Patients who have been treated with reirradiation for recurrent glioma reported survival benefits. This study aims to investigate whether re-irradiation of recurrent glioma with 45Gy dose can increase the overall survival of patients. Material and Methods A retrospective analysis of 35 patients re-irradiated for high-grade glioma recurrence between 2012 and 2020 was performed. All included patients met the following criteria: a) histopathological confirmation of primary brain cancer at initial diagnosis; b) a history of initial primary radiation; c) histological and/or imaging modality confirmation of recurrence. Outcome metrics included overall survival, prognostic factors for survival, and treatment-related toxicity. Results After the end of re-irradiation the median overall survival was 11 months (95% confidence interval, 7-14 months). From the patients evaluated in the current study after the end of re-irradiation the progression free survival was 6 months (3.8 - 8 months) while after the end of first radiation was 13 months (8 - 17.9 months). Our findings suggest that re-irradiation might prolong survival rates. Conclusion Recurrent Glioblastoma WHO IV is associated with a median overall survival of less than a year and the majority of patients have profound tumor-related symptoms .The results of this study suggest that re-irradiation may prolong the overall survival.
KS02.7.A Impact of FET PET on multidisciplinary neurooncological tumor board decisions in patients with brain tumors
Authors: G S Ceccon, J Werner, M I Ruge, R Goldbrunner, E Celik, C Baues, M Deckert, A Brunn, R Büttner, H Golla, L Nogova, M Schlamann, C Kabbasch, D Rueß, J Hampl, M Wollring, E K Bauer, C Tscherpel, G R Fink, K Langen, N Galldiks
Journal: Neuro-Oncology (2022)

Abstract Background Following neurooncological treatment of brain tumors, neurooncologists are often confronted with equivocal MRI findings (e.g., treatment-related changes such as pseudoprogression, non-measurable contrast-enhancing lesions, T2/FLAIR signal alterations, pseudoresponse). Especially in Europe, amino-acid PET is increasingly integrated into multidisciplinary neurooncological tumor boards (MNTB) to overcome these diagnostic uncertainties. We evaluated the correctness of MNTB decisions, in which amino acid PET findings were taken into account. Material and Methods In a single-university center study, we retrospectively evaluated 182 MNTB decisions of 154 patients with histomolecularly defined WHO grade 3 or 4 gliomas (n=123), including glioblastoma (n=80), anaplastic glioma (n=42), and gliosarcoma (n=1), or brain metastases (n=31) secondary to lung cancer, melanoma, breast cancer, or colorectal cancer presenting equivocal MRI findings following anticancer treatment. All patients underwent O-(2-[18F]-fluoroethyl)-L-tyrosine (FET) PET imaging as an adjunct for decision-making. Additionally, the patients’ clinical status, pretreatment, and conventional MRI findings were considered for decision-making. The presence of neoplastic tissue was considered if the mean FET uptake as assessed by tumor-to-brain ratios was &amp;gt; 2.0. MNTB decisions were validated using the neuropathological result in 42% (n=77) or clinicoradiologically in 58% (n=105). The diagnostic performance of MTNB decisions was evaluated using 2x2 contingency tables. Results The validation of all 182 MNTB recommendations, which integrated FET PET in the decision-making process, were correct in 95% (sensitivity, 97%; specificity, 75%; positive predictive value, 96%). Due to tumor progression, MNTB recommendations prompted a treatment change in 88% (n=160 of 182 decisions). When FET PET findings suggested progressive disease (n=157), MNTB decisions were correct in 96% (positive predictive value, 97%). In 22 MNTB decisions with the recommendation to continue the current treatment regimen, 82% were correctly identified as treatment-related changes. Conclusion FET PET seems to have a significant impact on MNTB decisions. A prospective evaluation of MNTB decisions with and without the integration of FET PET is warranted to define the added value of FET PET.